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IL-28B is a Key Regulator of B- and T-Cell Vaccine Responses against Influenza

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IL-28B genotype significantly impacts Influenza H1N1-stimulated immune responses in transplant recipients.

(A) Percent seroconversion to at least one influenza strain antigen in T/T (major) versus T/G or G/G (minor) IL-28B SNP in transplant recipients (rs8099917). Chi2 test was used to determine significance. (B) Percent seroconversion to at least one influenza strain antigen in T/T vs. T/G vs. G/G IL-28B SNP in transplant recipients (rs8099917). (C) Percent seroconversion to at least one influenza strain antigen in T/T (major) versus T/G or G/G (minor) IL-28B SNP in transplant recipients (rs8099917) receiving 2 g or more mycophenolate mofetil (MMF) per day. (D) Percent seroprotection to at least one influenza strain antigen in T/T (major) versus T/G or G/G (minor) IL-28B SNP in transplant recipients (rs8099917). Chi2 test was used to determine significance. (E) Percent seroprotection to at least one influenza strain antigen in T/T vs. T/G vs. G/G IL-28B SNP in transplant recipients (rs8099917). (F) Percent seroprotection to at least one influenza strain antigen in T/T (major) versus T/G or G/G (minor) IL-28B SNP in transplant recipients (rs8099917) receiving 2 g or more mycophenolate mofetil (MMF) per day. (G) Analysis of H1N1-stimulated Th1 cytokine release in transplant recipients with seroconversion against H1N1 Influenza from post–vaccine samples stratified according to IL-28B minor or major-allele genotypes. The rs8099917 TT (major allele, n = 7) compared to non-TT (minor allele, n = 7) genotypes are shown. Peripheral blood mononuclear cells (PBMCs) were stimulated overnight with inactivated Influenza A/H1N1 (0.3 µg/mL hemagglutinin). The expression profile of 17 cytokines was determined using a luminex-based platform. Key representative Th1 cytokines are shown. Mann Whitney U (MWU)-test determined statistically significant differences between groups; bars show median values (C–F). For some individuals the cytokine values were below the limit of detection and thus were given values of the lowest value in the linear range of the assay. (H) Frequency of post-vaccine H1N1-specific Interleukin (IL)-4 producing CD4+ T-cells in transplant recipients with seroconversion according to IL-28B genotype (rs8099917, n = 7 each). For flow cytometry gating strategy see S4 Figure. In PBMCs with a TT genotype 28.6% showed a >2-fold increase from unstimulated samples vs. H1N1 stimulated samples. In PBMCs with a no-TT genotype 85.7% showed a >2-fold increase from unstimulated samples vs. H1N1 stimulated samples (p = 0.031). (I) HLA-DR surface expression (mean fluorescent intensity (MFI)) on H1N1-stimulated naïve B-cells (CD20+CD27) in transplant recipients stratified according to the IL-28B genotype (rs8099917) for only those who seroconverted. PBMCs were stimulated with inactivated H1N1 influenza overnight. Baseline values represent non-antigen controls.

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doi: https://doi.org/10.1371/journal.ppat.1004556.g001